tbuckley/cabot-search huggingface dataset:
Molecular subtypes from comprehensive clustering from multi-omics dataset to predict the therapeutic efficacy of immunotherapeutic agent-based treatments in advanced hepatocellular carcinoma.
Authors: Hong Jae Chon, Sung Hwan Lee, Gwangil Kim, Haeyoun Kang, Jaekyung Cheon, Beodeul Kang, Chan Kim
Journal: Journal of Clinical Oncology (2023)

4112 Background: In advanced hepatocellular carcinoma (HCC), combined treatment using anti-PD-L1 and anti-VEGF antibodies is a major therapeutic strategy in addition to using anti-PD-1 and anti-CTLA4 target agents. To identify clinically relevant molecular biomarkers for immunotherapeutic agents-based treatment in advanced HCC by comprehensive molecular profiling using genomics alterations and transcriptomic data. Methods: Multi-omics data from clinical tumor samples of patients treated with atezolizumab + bevacizumab (94 patients), nivolumab (40 patients), and ipilimumab + nivolumab (32 patients) were obtained from tumor biopsies or surgical resections in a single institution. The targeted panel sequencing was conducted via the Oncomine comprehensive assay (ThermoFisher, USA). QuantSeq mRNA sequencing (Lexogen, USA) was used to generate datasets for the genomic alterations and gene expression profiles. Results: A total of 166 target sequences for genomic alterations and 136 transcriptomic sequences were performed in patients with advanced HCC treated with immunotherapeutic agent-based treatment options. High tumor mutation burden was significantly associated with favorable therapeutic efficacy (disease control rate, P=0.036) and progression-free survival (P=0.037) in patients who had atezolizumab with bevacizumab treatment. The genomic alteration of CTNNB1 mutation correlated with the favorable therapeutic efficacy of nivolumab monotherapy (PFS, P=0.022), contrary to TP53 mutation (PFS, P=0.063) which demonstrated unfavorable outcomes. CD274(PD-L1) mRNA expression was significantly associated with a high drug response following nivolumab monotherapy (objective response rate, P=0.047) and oncologic outcomes (PFS, P=0.021). Interestingly, PLA2G4A, known as a downstream molecule of the VEGF signaling pathway, was highly correlated with unfavorable therapeutic efficacy of the combined atezolizumab with bevacizumab treatment (disease control rate, P=0.002) and related oncologic outcomes (PFS, P=0.003). We also identified the clinically relevant molecular subtypes from unbiased clustering using the ontologic pathway collection. We also used gene expression profiles to predict the therapeutic response and oncologic outcomes from immunotherapeutic agent-based treatment options. Conclusions: We identified clinically relevant molecular biomarkers from comprehensive clustering of a multi-omics dataset to predict the therapeutic efficacy and oncologic outcomes. Further prospective studies with clinical validation are warranted to confirm clinical implications.
15-month safety and efficacy data after intraperitoneal treatment with <sup>224</sup>Radium-labelled microparticles after CRS-HIPEC for peritoneal metastasis from colorectal cancer.
Authors: Stein G Larsen, Wilhelm Graf, Olaf Sørensen, Anthony Burton Mariathasan, Milan Spasojevic, Lana Ghanipour, Peter Cashin, Øyvind Bruland
Journal: Journal of Clinical Oncology (2023)

3518 Background: Peritoneal metastasis (PM) from colorectal cancer carries a dismal prognosis. Improved survival can be achieved by extensive cytoreductive surgery (CRS), frequently used together with hyperthermic intraperitoneal chemotherapy (HIPEC), with median time to recurrence around 12 months. Radspherin is a novel treatment principle based on the delivery of short range and cytotoxic alpha particles emitted during the decay of 224Ra. Alpha particles have high linear energy transfer and a radiation range less than 100 µm (3-10 cell diameters), generating highly localized and effective radiation with non-repairable double-strand DNA breaks in affected cells. Our hypothesis is that Radspherin produces an alpha-particle radiation field exclusively to the surfaces and liquid volumes of the peritoneum, delivering lethal doses to remaining micrometastasis in the peritoneal linings and eradicate free-floating tumor cells after surgical resection, thus assumingly prolonging time to recurrence and potentially overall survival. Methods: A phase 1/2a study (EudraCT 2018-002803-33) is ongoing to evaluate safety, tolerability and signal of efficacy of Radspherin injected intraperitoneally two days after CRS-HIPEC. After completion of dose escalation (1-2-4-7 MBq), an activity-dose of 7 MBq was recommended. Assessment of safety and efficacy (diagnostic imaging) was performed every three months. Safety data and progression-free survival (PFS) at 15 months are presented. Results: Twenty-three patients (pts) were enrolled across cohorts (safety population), of these 12 pts received the recommended dose of 7MBq, 9 pts single dose and 3 pts split dose (3,5 MBq x2). Twelve pts had synchronous PM and 11 metachronous PM. Median age was 64 years (28-78), 70 % were female and median peritoneal cancer index was 7 (3-19). To date, 271 adverse events (AE) were reported, whereof only 7 (all grade 1-2) were deemed related to Radspherin. Fourteen serious adverse events (SAEs) in 8 pts have been reported, none considered related to Radspherin. At 15 months, 9 out of 23 pts (39 %) had recurred, whereof 4 pts recurred in the peritoneum. In the expansion cohort (7MBq), 3 out of 12 pts (25 %) had recurred and none of these pts had peritoneal recurrences. Median PFS was not reached in the two populations. Conclusions: Radspherin was well tolerated with no related SAEs reported. At 15 months median PFS has not been reached and none of the patients at recommended dose had peritoneal recurrences. The results are encouraging and warrant further exploration of Radspherin as a novel treatment principle in clinical trials. Clinical trial information: NCT03732781 .
Real-world safety and effectiveness of MVASI in metastatic colorectal cancer patients in Canada.
Authors: Winson Y. Cheung, Setareh Samimi, Kim Ma, Gregory John Knight, Shaqil Nadirali Kassam, Bruce Colwell, Annie Beaudoin, Mark David Vincent, Mateya Trinkaus, Alain Filion, Hatim Karachiwala, Timothy Asmis, Lucas Sideris, Leyla Nunez, Rajvi Wani, Carlye Cirone Morris, Elaine Ngan, Yinhao Du, Naila Inam
Journal: Journal of Clinical Oncology (2023)

e15555 Background: MVASI is a biosimilar to the reference product, bevacizumab, and is the first biosimilar approved by Health Canada for the first-line (1L) treatment of metastatic colorectal cancer (mCRC). This study addresses the limited real-world evidence by describing the safety and effectiveness of MVASI as 1L therapy in mCRC. Methods: Retrospective data were collected in two waves of sites across Canada, at least 1 year (wave 1) or 2 years (wave 2) after commercial availability of MVASI at each site. Adult patients treated with ≥ 1 MVASI cycles as their 1L therapy for mCRC were included. Baseline demographic and clinical characteristics were collected 6 months prior to MVASI initiation (index date). Medical history, adjuvant treatment, and CRC diagnosis were collected within 5 years of pre-index date. Outcomes were gathered between index and chart review dates. Results: Among the 75 patients in wave 1, 36 (48.0%) were male and the median age was 62 years. Of the 164 patients in wave 2, 98 (59.8%) were male and the median age was 67 years. Most patients in wave 1 (42/69; 60.9%) and wave 2 (87/141; 61.7%) had a RAS mutation. The median time from mCRC diagnosis to MVASI initiation among wave 1 and 2 patients was 3.1 (IQR [2.1, 4.2]) and 2.3 months (IQR [1.6, 3.7]), respectively. At least one safety event of interest (EOI) was recorded for 26/75 (34.7%) wave 1 and 70/164 (42.7%) wave 2 patients (Table 1). The median progression free survival (PFS) for wave 1 and 2 patients were 9.47 and 21.38 months, respectively. Median overall survival (OS) for wave 1 patients was not estimable and was 26.45 months for wave 2 patients. Conclusions: In this real-world study, mCRC patients treated with 1L MVASI were generally representative of the Canadian mCRC population treated with 1L bevacizumab. Compared with clinical trials of MVASI and reference bevacizumab, the EOI profile and the OS data are similar, but lower rates of individual EOIs are observed in this real-world setting. The shorter PFS observed in wave 1 may be due to higher rates of comorbidities at baseline and longer time from mCRC diagnosis to index. [Table: see text]
SWOG S1823/CCTG GCC1: Translational observational investigational study of the liquid biomarker microRNA 371a-3p in newly diagnosed germ cell tumours—Real-world trial design, rapid accrual, and robust secondary use of data opportunities.
Authors: Antoine Morin Coulombe, Guliz Ozgun, Rebecca Johnson, Mark Andrew Lewis, Nabil Adra, Scott E. Eggener, Bruce J. Roth, Christopher W. Ryan, Christopher Porter, Fred Millard, Thomas Jang, Robert James Hamilton, Lawrence H. Einhorn, Christian K. Kollmannsberger, Kathryn B. Arnold, Charles David Blanke, Siamak Daneshmand, Craig R. Nichols, Lucia Nappi, Andrea Harzstark
Journal: Journal of Clinical Oncology (2023)

TPS5103 Background: With the discovery of the very promising, germ cell malignancy (GCM) specific, liquid biomarker microRNA 371a-3p (miR371), the investigative trajectory has markedly accelerated. With its outstanding, previously-reported specificity and positive predictive value, miR371 likely will become a powerful tool for clinical decision-making. The primary objective of SWOG S1823/CCTG GCC1 [NCT03067181] is to define the operating characteristics of plasma miR371 expression at the time of clinical relapse for low/moderate risk non-seminoma GCM patients on active surveillance. Methods: S1823 is a prospective, observational, adult GCM translational trial which is actively accruing. Broad eligibility includes all newly diagnosed adult GCM patients. Patients are assigned to low (&lt;25% risk of relapse), moderate (25-90% risk of relapse) or high (≥90% risk of harboring active GCM) risk groups. Pragmatic logistics include using Streck tubes and centralized processing for miR371 sample processing and analytics. Research samples were drawn at the time of routine blood draws minimizing patient burden. Source documents are submitted along with case report forms. This data-gathering model gives an important data quality-control check. S1823 began in July 2020 and has since accelerated its accrual to consistently predicted new enrollments of 20-30 cases/month. As of January 2023, the study enrolled 389 low-risk, 114 moderate-risk and 146 high-risk patients (657 total). Interim analysis is planned at the time 40 non-seminoma GCM patients have relapsed and is anticipated in late 2023 to early 2024. 404 centers have opened S1823. 3 Canadian centers have enrolled &gt;10 patients (range 11-51). 17 USA institutions have enrolled &gt;10 patients (range 11-112). In North America, 9 of the 12-storied GCM clinical research programs have had robust participation. The leading accruing organization was the Kaiser Permanente system where 112 patients have been enrolled. In Canada, all population centers contributed proportionally. In the USA, the dominant enrollment comes from the west coast and mid-west. Proportional enrollments have been seen in Hispanic and Asian populations. The entire study provides rich opportunities for a variety of secondary use and patterns of care projects that will begin to roll out over the next year. Clinical trial information: NCT03067181 . [Table: see text]
Risk of immune-related adverse events (irAE) with immune checkpoint inhibitors (ICI) in patients (pts) with family history (FH) of autoimmune disease (AID).
Authors: Piyush Grover, Isabel Li, Alexander M. Menzies, Georgina V. Long
Journal: Journal of Clinical Oncology (2023)

2648 Background: Pts with personal history (PH) of AID are at increased risk of irAE following ICI. Risk of irAE in pts with FH of AID is unknown. Methods: In this retrospective cohort study, consecutive pts were recruited from 2 Australian melanoma cancer centers. Pts who received anti-PD-1 (PD1) based ICI with FH of AID were eligible. Pts with PH of AID were excluded. Toxicity data (CTCAE v5.0) was obtained and stratified by FH of AID (first/second/third degree relative). Descriptive statistics and Fisher’s Exact test were used for analysis. Results: 396 melanoma cases were screened, of which 44 (11.1%) were eligible for inclusion. Baseline characteristics are summarized. 57 irAE occurred in 44 pts. The most common irAE were dermatological (n=11; 19.3%), colitis (n=8; 14.0%), endocrinopathies (n=8; 14.0%), hepatitis (n=7; 12.3%) and arthritis (n=7; 12.3%). Among 57 irAE, frequency of Grade 1,2,3 and 4 irAE was 16 (28.1%), 26 (45.6%), 12 (21.0%) and 3 (5.3%) respectively. Corticosteroids were used for 31 (54.4%) irAE. Hospital admission for management of irAE occurred in 11 pts (25.0%). ICI was discontinued in 20 pts (45.5%) due to irAE. In pts with irAE, FH of that irAE/AID was present in 6 pts (13.6%) (n= 2 x arthritis, n= 2 x psoriasis, n= 1 x Crohn’s disease, n= 1 x Grave’s disease), and 4 of these patients had a first-degree relative with an AID. 3/6 pts had ICI ceased due to an irAE (peak toxicity Grade was 3) and 4/6 pts had RECIST response. There was no association in development of irAE between patients with FH of AID in a first-degree relative and those with FH of AID in second or third degree relative (p=0.17). Rate of irAE in pts with FH of AID was not statistically higher to that reported in registration trials of similar regimens (p=0.40). Conclusions: FH of AID is common in melanoma pts and was not associated with higher rate or morbidity of irAE. FH AID should be routinely collected, and larger scale studies need to be performed. [Table: see text]
MATRIX plasma-in-plasma contrived samples assessment and detection of MRD using the Personalis NeXT Personal assay.
Authors: Paul Labrousse
Journal: Journal of Clinical Oncology (2023)

e15056 Background: Detection of circulating tumor DNA (ctDNA) has been shown to correlate with clinical outcome of oncology patients. Molecular residual disease (MRD) profiling by ctDNA is being rapidly deployed. Current tumor-informed MRD tests assess a relatively small number of personalised variants, placing limits on their detection sensitivity and ultimately leading to false-negative results due to insufficient assay limit of detection (LOD). Here we report a performance evaluation of the Personalis NeXT Personal tumor-informed MRD assay, using a novel design for contrived samples that are highly commutable to clinical samples, enabling robust assessment of these emerging MRD assays. Methods: Our novel samples were built from commercially acquired matched tumor and plasma samples, across different indications. The cancer plasma was diluted into a background of healthy donor plasma to create the 72 plasma-in-plasma samples in each study (total of 144). Personalis performed WGS on the matched solid tumor and normal samples from each patient. ~1800 somatic variants were selected for each patient. A personalized panel was designed and used to enrich for the selected targets in the individual plasma samples. An aggregated positive variant score was evaluated to determine the presence of ctDNA in each plasma sample. Results: MATRIX 1 panels averaged 1863 variants (range: 1818 to 1888) selected for MRD tracking. With 152 clinically relevant variants and additional assay components, an average of 2206 variants were assessed per patient. MATRIX 2 panels averaged 1836 variants (range: 1819 to 1867) selected for MRD tracking. With 2130 clinically relevant variants they averaged 4094 variants assessed per patient. In the MATRIX 1 study, tumor signal was detected in all analyzed samples, including 9 samples at 0.002% tumor plasma dilution, with an assay sensitivity of 100%. The MATRIX 2 study showed tumor signal detected in 14 of 16 samples at 0.001% tumor plasma dilution. The 2 false negatives were reported at the 0.001% tumor plasma dilution. Thus, the assay sensitivity was 87.5% at the lowest dilution (0.001%) and 96.8% overall. Conclusions: The MATRIX plasma-in-plasma approach is a robust option for assessing the sensitivity of MRD assays to low levels of ctDNA. This approach addresses all parts of an MRD assay for both the plasma and tumor/normal tissues, and is the closest thing to real clinical samples while allowing direct interrogation of sensitivity. Additionally, it allows assessment of any genomic or epigenomic biological feature. The Personalis NeXT Personal assay shows ultra-high sensitivity with reproducible data down to the 1-3 PPM range, and expansion of the personalized panel fixed clinical content allows tracking of more driver and resistance mutations with no impact to the MRD sensitivity.
Chemotherapeutic sensitivity in colorectal cancer expressing low RNA of wild type homologous recombination genes.
Authors: Daniel Walden, Sachin Deshmukh, Felipe Batalini, Binbin Zheng-Lin, Sharon Wu, Joanne Xiu, Bennett Adam Caughey, John H Strickler, Wolfgang Michael Korn, Emil Lou, Daniel H. Ahn, Christina Wu, Sanjay Goel, Anthony F. Shields, Tanios S. Bekaii-Saab
Journal: Journal of Clinical Oncology (2023)

3531 Background: Homologous recombination deficient (HRD) colorectal cancer (CRC) has improved overall survival (OS) when exposed to DNA damaging agents (DDA) oxaliplatin (OX) and irinotecan (IR). However, this OS benefit is only observed in HRD mutated CRC. Low expression of wild type (WT) BRCA1 RNA displays prolonged OS in ovarian cancer; this finding has not been investigated in CRC or outside BRCA. We investigate if low expression of WT HR genes is associated with prolonged OS in response to DDA. Methods: A total of 12,860 CRC patients tumor biopsies were analyzed by next-generation sequencing (592, NextSeq; WES, WTS NovaSeq). Patients with HRD mutations and MSI-H were excluded (N = 935). 11,925 patients were included in the analysis. A total of 11 core ( BARD1, BLM, BRCA1, BRCA2, BRIP1, MRE11, NBN, PALB2, RAD50, RAD51, RAD51B) and 7 related ( BAP1, WRN, DNMT3A, ERCC1, FANCA, FANCF, RECQL4) HR genes were analyzed. Samples were classified by RNA expression percentiles within the studied cohort. Real world OS was extracted from insurance claims and calculated using Kaplan-Meier estimates for molecularly defined cohorts from first of OX or IR to last contact. Results: OS benefit is seen in low RNA expression (bottom 10%) compared to high expression (top 10%) of all core WT HR genes except RAD51B, BARD1 and BRCA2 in response to IR. We observe a progressively longer OS with lower associated RNA expression in response to DDA. OS of nearly 7 years was observed in low expressing BRCA1 and RAD51 following IR exposure and 4.5-year OS benefit when compared to high expression of these genes. OS benefit in response to OX was less robust but significantly prolonged in BRCA1 and BRIP1 (Table). Patients harboring HRD mutations had similar OS to WT HR RNA low (bottom 10%) in response to OX (HR = 0.75; p = 0.1) and IR (HR = 0.82; p = 0.36). Conclusions: Here we report a novel subclass of CRC defined as patients with low RNA expressing WT HR genes that exhibit differential sensitivity to DDA. Significantly longer survival is noted in CRC with low expression BRCA1, RAD51 and BLM, while post-OX survival was significantly prolonged with low expression of BRCA1, BRIP1 and FANCA. Further characterization of sensitive HR genes will better predict DDA sensitivity and impact treatment sequencing. [Table: see text]
Mismatch Repair system protein deficiency as a factor of resistance to chemo-radiotherapy treatment in patients with locally advanced rectal adenocarcinoma and its influence on disease-free survival.
Authors: Andrea Pretta, Pina Ziranu, Riccardo Giampieri, Clelia Donisi, Giovanna Pinna, Giovanni Randon, Francesco Loi, Giulia Deias, Enrico Palmas, Federica Morano, Cinzia Solinas, Eleonora Lai, Valeria Pusceddu, Marco Puzzoni, Luigi Zorcolo, Raffaele Barbara, Gavino Faa, Rossana Berardi, Filippo Pietrantonio, Mario Scartozzi
Journal: Journal of Clinical Oncology (2023)

3615 Background: Available data on Mismatch Repair system deficit and microsatellite instability are conflicting and are generally derived from a small number of patients due to the rarity of this condition in rectal cancer. Our study aimed to evaluate the frequency and therapeutic implications of Mismatch Repair proteins (MMR) status in patients with locally advanced rectal cancer (LARC). Methods: We retrospectively collected data from 318 patients affected by LARC adenocarcinoma (cT3-4 +/- N1-2) treated at the Medical Oncology Unit of the University Hospital of Cagliari, Italy, the Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy and at the Medical Oncology Unit, AOU Ospedali Riuniti, Ancona. Italy. All patients included in the study underwent neoadjuvant concurrent capecitabine and long-course radiotherapy (RT) (total dose of Gy 50.4), afterwards a total mesorectal excision (TME) was performed. MMR expression was evaluated through immunohistochemistry. The primary objective was major TRG (0-1 Ryan’s score) while secondary objectives were pathological complete response, disease-free survival (DFS) and overall survival (OS). Results: 160 patients (148 pMMR and 12 dMMR) were included in exploratory cohort and 158 (146 pMMR and 12 dMMR) were included in validation cohort. A major TRG has been shown in 64/148 (42,6%) and 63/146 (43,1%) patients with pMMR in exploratory cohort and validation cohort, respectively; while no major TRG have been shown in dMMR patients in exploratory cohort nor in validation cohort. Both exploratory and validation cohorts showed a statistically significant higher median DFS in pMMR patients compared to dMMR ones: NR vs 14 months in exploratory cohort ( p = 0,003) and NR vs 17 months in validation cohort ( p = 0,02). Conclusions: Our retrospective study indicated an association between dMMR and poor or no response to preoperative chemoradiotherapy. These results are consistent with the role of MMR as a predictor of poor-response to chemoradiotherapy and represent a hypothesis-generating study for the selection of these patients for immunotherapy in the neoadjuvant setting, in which the available data are immature.